A unique three-dimensional model for evaluating the impact of therapy on multiple myeloma
| Autor: | Tony Reiman, Julia Kirshner, Andrew Belch, Kyle J. Thulien, Linda M. Pilarski, Lorri D. Martin, Carina Debes Marun |
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| Rok vydání: | 2008 |
| Předmět: |
Pathology
medicine.medical_specialty Stromal cell Plasma Cells Immunology Drug Evaluation Preclinical Clone (cell biology) Biology Plasma cell Models Biological Biochemistry Bortezomib Bone Marrow hemic and lymphatic diseases Tumor Cells Cultured medicine Animals Humans Melphalan Multiple myeloma Cell Proliferation Chromosome Aberrations Cell Biology Hematology medicine.disease Boronic Acids Clone Cells Hematopoiesis Rats Haematopoiesis medicine.anatomical_structure Drug Resistance Neoplasm Pyrazines Neoplastic Stem Cells Cancer research Bone marrow Stromal Cells Stem cell Multiple Myeloma medicine.drug |
| Zdroj: | Blood. 112:2935-2945 |
| ISSN: | 1528-0020 0006-4971 |
| DOI: | 10.1182/blood-2008-02-142430 |
| Popis: | Although the in vitro expansion of the multiple myeloma (MM) clone has been unsuccessful, in a novel three-dimensional (3-D) culture model of reconstructed bone marrow (BM, n = 48) and mobilized blood autografts (n = 14) presented here, the entire MM clone proliferates and undergoes up to 17-fold expansion of malignant cells harboring the clonotypic IgH VDJ and characteristic chromosomal rearrangements. In this system, MM clone expands in a reconstructed microenvironment that is ideally suited for testing specificity of anti-MM therapeutics. In the 3-D model, melphalan and bortezomib had distinct targets, with melphalan targeting the hematopoietic, but not stromal com-partment. Bortezomib targeted only CD138+CD56+ MM plasma cells. The localization of nonproliferating cells to the reconstructed endosteum, in contact with N-cadherin–positive stroma, suggested the presence of MM-cancer stem cells. These drug-resistant CD20+ cells were enriched more than 10-fold by melphalan treatment, exhibited self-renewal, and generated clonotypic B and plasma cell progeny in colony forming unit assays. This is the first molecularly verified demonstration of proliferation in vitro by ex vivo MM cells. The 3-D culture provides a novel biologically relevant preclinical model for evaluating therapeutic vulnerabilities of all compartments of the MM clone, including presumptive drug-resistant MM stem cells. |
| Databáze: | OpenAIRE |
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